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Stimulation of tissue-type plasminogen activator expression by retinoic acid in human endothelial cells requires retinoic acid receptor β2 induction

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Author: Lansink, M. · Kooistra, T.
Institution: Gaubius Laboratory, Leiden, Netherlands Gaubius Laboratory TNO-PG, P.O. Box 2215, 2301 CE Leiden, Netherlands TNO Preventie en Gezondheid
Source:Blood, 2, 88, 531-541
Identifier: 233401
Keywords: Biology · Antisense oligodeoxynucleotide · Cycloheximide · Tetinoic acid receptor · Alternative rna splicing · Antibody response · Cell stimulation · competitive inhibition · Endothelium cell · Enzyme active site · Fibrinolysis · Gene induction · Human cell · Protein degradation · Base Sequence · Benzoates · Cells, Cultured · Chromans · Cycloheximide · DNA, Complementary · Endothelium, Vascular · Gene Expression Regulation · Humans · Molecular Sequence Data · Oligonucleotides, Antisense · Protein Synthesis Inhibitors · Receptors, Retinoic Acid · Tissue Plasminogen Activator · Tretinoin · Umbilical Veins


We previously showed the involvement of retinoic acid receptor α (RARα) in the induction of tissue-type plasminogen activator (t-PA) synthesis by RA in human umbilical vein endothelial cells (HUVECs). However, the rather slow onset of this induction of t-PA synthesis suggested an indirect role of RARα. Here, we show that the protein synthesis inhibitor, cycloheximide completely blocks the induction of t-PA by RA, which points to the need of an intermediary protein in t-PA stimulation. This intermediary protein is likely to be RARβ2 on the basis of the following findings: (1) the induction of RARβ by RA exactly precedes that of t-PA; (2) HUVECs with elevated RARβ mRNA levels show an undelayed t-PA induction on stimulation with RA, and this response can be almost completely inhibited with an RAR antagonist; and (3) an antisense oligodeoxynucleotide against the translation initiation site of RARβ2 mRNA greatly reduces the t-PA induction by RA. Thus, induction of t-PA by RA in HUVECs involves a 2-step mechanism requiring induction of RARβ2 via RARα, followed by induction of t-PA synthesis via RARβ2. Each of these steps is shown to have a different activation profile with RA and 9-cis RA. Chemicals/CAS: Benzoates; Chromans; Cycloheximide, 66-81-9; DNA, Complementary; Oligonucleotides, Antisense; Protein Synthesis Inhibitors; Receptors, Retinoic Acid; retinoic acid receptor alpha; retinoic acid receptor beta; Ro 41-5253, 144092-31-9; Tissue Plasminogen Activator, EC; Tretinoin, 302-79-4